tbuckley/cabot-search huggingface dataset:
Frequency of Biopsy and Tumor Grade Before vs After Introduction of Prostate Magnetic Resonance Imaging
Authors: David Robinson, Rafid Abdulkareem, Delshad Nasrollah, Anders Ljung, Per Hintze, Sara Wallby, Henriettæ Ståhlbrandt, Thorun Frennvall, Johan Styrke, Pär Stattin, Hans Garmo
Journal: JAMA Network Open (2023)

Importance In randomized clinical trials (RCTs), magnetic resonance imaging (MRI) before prostate biopsy has been associated with fewer biopsies, decreased detection of Gleason score 6 cancers, and increased detection of Gleason score 7 or higher cancers. Objective To study whether MRI of the prostate before the decision to biopsy is associated with biopsy frequency and distribution of Gleason score in clinical practice. Design, Setting, and Participants This is a retrospective, population-based cohort study of men in Jönköping Region, Sweden. Men with prostate-specific antigen (PSA) level measured between November 2011 and 2020 were monitored until January 31, 2021. Men with known prostate cancer were excluded. Data analysis was performed from July to December 2022. Exposures Data on repeated PSA measures, prostate biopsies, and MRI prostate were extracted from health care records, and cancer characteristics were obtained from The National Prostate Cancer Register. Main Outcomes and Measures The proportions of men who underwent prostate biopsy and risk of Gleason score 6 or Gleason score 7 or higher cancer and negative biopsy before and after introduction of MRI were calculated. Results In this cohort study of 23 802 men (mean [SD] age, 60.8 [13.6] years) who underwent PSA testing, when the use of MRI increased, fewer biopsies were performed (adjusted odds ratio [OR], 0.84; 95% CI, 0.72-0.97) and the odds of detecting Gleason score 6 cancer decreased (OR, 0.47; 95% CI, 0.33-0.64), whereas the odds of detecting Gleason score 7 or higher cancer increased (OR, 1.24; 95% CI, 1.02-1.50). Conclusions and Relevance In this study, the introduction of MRI to clinical practice was associated with a decreased proportion of men who underwent a biopsy and decreased detection of Gleason score 6 cancer but increased detection of Gleason score 7 or higher cancer. These clinical data support the use of prostate MRI before biopsy in an effort to avoid unnecessary biopsies.
Brain α2δ-1–Bound NMDA Receptors Drive Calcineurin Inhibitor–Induced Hypertension
Authors: Jing-Jing Zhou, Jian-Ying Shao, Shao-Rui Chen, Hui-Lin Pan
Journal: Circulation Research (2023)

BACKGROUND: Calcineurin is highly enriched in immune T cells and the nervous system. Calcineurin inhibitors, including cyclosporine and tacrolimus (FK506), are the cornerstone of immunosuppressive regimens for preserving transplanted organs and tissues. However, these drugs often cause persistent hypertension owing to excess sympathetic outflow, which is maintained by N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory input to the hypothalamic paraventricular nucleus (PVN). It is unclear how calcineurin inhibitors increase NMDAR activity in the PVN to augment sympathetic vasomotor activity. α2δ-1 (encoded by the Cacna2d1 gene), known colloquially as a calcium channel subunit, is a newly discovered NMDAR-interacting protein. In this study, we determined whether α2δ-1 plays a role in calcineurin inhibitor–induced synaptic NMDAR hyperactivity in the PVN and hypertension development. METHODS: Immunoblotting and coimmunoprecipitation assays were used to quantify synaptic protein levels and the physical interaction between GluN1 (the obligatory NMDAR subunit) and α2δ-1. Whole-cell patch-clamp recordings of retrogradely labeled, spinally projecting PVN were conducted in perfused brain slices to measure presynaptic and postsynaptic NMDAR activity. Radio-telemetry was implanted in rodents to continuously record arterial blood pressure in conscious states. RESULTS: Prolonged treatment with FK506 in rats significantly increased protein levels of α2δ-1, GluN1, and the α2δ-1-GluN1 complex in PVN synaptosomes. These effects were blocked by inhibiting α2δ-1 with gabapentin or interrupting the α2δ-1-NMDAR interaction with an α2δ-1 C-terminus peptide. Treatment with FK506 potentiated the activity of presynaptic and postsynaptic NMDARs in spinally projecting PVN neurons; such effects were abolished by gabapentin, Cacna2d1 knockout, or α2δ-1 C-terminus peptide. Furthermore, microinjection of α2δ-1 C-terminus peptide into the PVN diminished renal sympathetic nerve discharges and arterial blood pressure that had been increased by FK506 treatment. Remarkably, concurrent administration of gabapentin prevented the development of FK506-induced hypertension in rats. Additionally, FK506 treatment induced sustained hypertension in wild-type mice but not in Cacna2d1 knockout mice. CONCLUSIONS: α2δ-1 is essential for calcineurin inhibitor–induced increases in synaptic NMDAR activity in PVN presympathetic neurons and sympathetic outflow. Thus, α2δ-1 and α2δ-1-bound NMDARs represent new targets for treating calcineurin inhibitor–induced hypertension. Gabapentinoids (gabapentin and pregabalin) could be repurposed for treating calcineurin inhibitor–induced neurogenic hypertension.
PrEParing for the End of the HIV Epidemic—A Public Health Imperative
Authors: Roger J. Bedimo, Tomasz Jodlowski
Journal: JAMA Network Open (2023)

US Preventive Services Task Force; Michael J. Barry, MD; Wanda K. Nicholson, MD, MPH, MBA; Michael Silverstein, MD, MPH; David Chelmow, MD; Tumaini Rucker Coker, MD, MBA; Esa M. Davis, MD, MPH; Katrina E. Donahue, MD, MPH; Carlos Roberto Jaén, MD, PhD, MS; Marti Kubik, PhD, RN; Li Li, MD, PhD, MPH; Gbenga Ogedegbe, MD, MPH; Goutham Rao, MD; John M. Ruiz, PhD; James J. Stevermer, MD, MSPH; Joel Tsevat, MD, MPH; Sandra Millon Underwood, PhD, RN; John B. Wong, MD
Dual‐Targeting Nanoliposome Improves Proinflammatory Immunomodulation of the Tumor Microenvironment
Authors: Zili Gu, Candido G. da Silva, Sen Ma, Qi Liu, Timo Schomann, Ferry Ossendorp, Luis J. Cruz
Journal: Advanced Healthcare Materials (2023)

Abstract Immunotherapies targeting immune checkpoints have revolutionized cancer treatment by normalizing the immunosuppressive microenvironment of tumors and reducing adverse effects on the immune system. Indoleamine 2,3‐dioxygenase (IDO) inhibitors have garnered attention as a promising therapeutic agent for cancer. However, their application alone has shown limited clinical benefits. Cabozantinib, a multitarget tyrosine kinase inhibitor, holds immunomodulatory potential by promoting infiltration and activation of effector cells and inhibiting suppressive immune cells. Despite its potential, cabozantinib as a monotherapy has shown limited efficacy in terms of objective response rate. In this study, IDO‐IN‐7 and cabozantinib are coencapsulated into liposomes to enhance tumor accumulation and minimize adverse effects. The liposomal combination exhibits potent cytotoxicity and inhibits the function of IDO enzyme. Furthermore, the dual‐targeted treatment effectively inhibits tumor development and reverses the suppressive tumor microenvironment by regulating both adaptive and innate branch of immune system. This is evidenced by pronounced infiltration of T cells and B cells, a decrease of regulatory T lymphocytes, a shift to a proinflammatory phenotype of tumor‐associated macrophages, and increases levels of neutrophils. This is the first developed of a liposome‐delivered combination of IDO inhibitors and cabozantinib, and holds great potential for future clinical application as a promising anticancer strategy.
Aspirin for Secondary Prevention of Cardiovascular Disease in 51 Low-, Middle-, and High-Income Countries
Authors: Sang Gune K. Yoo, Grace S. Chung, Silver K. Bahendeka, Abla M. Sibai, Albertino Damasceno, Farshad Farzadfar, Peter Rohloff, Corine Houehanou, Bolormaa Norov, Khem B. Karki, Mohammadreza Azangou-Khyavy, Maja E. Marcus, Krishna K. Aryal, Luisa C. C. Brant, Michaela Theilmann, Renata Cífková, Nuno Lunet, Mongal S. Gurung, Joseph Kibachio Mwangi, Joao Martins, Rosa Haghshenas, Lela Sturua, Sebastian Vollmer, Till Bärnighausen, Rifat Atun, Jeremy B. Sussman, Kavita Singh, Sahar Saeedi Moghaddam, David Guwatudde, Pascal Geldsetzer, Jennifer Manne-Goehler, Mark D. Huffman, Justine I. Davies, David Flood
Journal: JAMA (2023)

Importance Aspirin is an effective and low-cost option for reducing atherosclerotic cardiovascular disease (CVD) events and improving mortality rates among individuals with established CVD. To guide efforts to mitigate the global CVD burden, there is a need to understand current levels of aspirin use for secondary prevention of CVD. Objective To report and evaluate aspirin use for secondary prevention of CVD across low-, middle-, and high-income countries. Design, Setting, and Participants Cross-sectional analysis using pooled, individual participant data from nationally representative health surveys conducted between 2013 and 2020 in 51 low-, middle-, and high-income countries. Included surveys contained data on self-reported history of CVD and aspirin use. The sample of participants included nonpregnant adults aged 40 to 69 years. Exposures Countries’ per capita income levels and world region; individuals’ socioeconomic demographics. Main Outcomes and Measures Self-reported use of aspirin for secondary prevention of CVD. Results The overall pooled sample included 124 505 individuals. The median age was 52 (IQR, 45-59) years, and 50.5% (95% CI, 49.9%-51.1%) were women. A total of 10 589 individuals had a self-reported history of CVD (8.2% [95% CI, 7.7%-8.6%]). Among individuals with a history of CVD, aspirin use for secondary prevention in the overall pooled sample was 40.3% (95% CI, 37.6%-43.0%). By income group, estimates were 16.6% (95% CI, 12.4%-21.9%) in low-income countries, 24.5% (95% CI, 20.8%-28.6%) in lower-middle-income countries, 51.1% (95% CI, 48.2%-54.0%) in upper-middle-income countries, and 65.0% (95% CI, 59.1%-70.4%) in high-income countries. Conclusion and Relevance Worldwide, aspirin is underused in secondary prevention, particularly in low-income countries. National health policies and health systems must develop, implement, and evaluate strategies to promote aspirin therapy.
Regorafenib plus Vincristine and Irinotecan in Pediatric Patients with Recurrent/Refractory Solid Tumors: An Innovative Therapy for Children with Cancer Study
Authors: Michela Casanova, Francisco Bautista, Quentin Campbell-Hewson, Guy Makin, Lynley V. Marshall, Arnauld C. Verschuur, Adela Cañete Nieto, Nadège Corradini, Bart A. Ploeger, Barbara J. Brennan, Udo Mueller, Hong Zebger-Gong, John W. Chung, Birgit Geoerger
Journal: Clinical Cancer Research (2023)

This phase Ib study defined the safety, MTD, and recommended phase II dose (RP2D) of regorafenib combined with vincristine and irinotecan (VI). Secondary objectives were evaluation of antitumor activity and pharmacokinetics (PK) of regorafenib and irinotecan.Patients aged 6 months to <18 years with relapsed/refractory solid malignancies [≥50% with rhabdomyosarcoma (RMS)] received regorafenib (starting dose 72 mg/m2/day) concomitantly or sequentially with vincristine 1.5 mg/m2 on days 1 and 8, and irinotecan 50 mg/m2 on days 1-5 (21-day cycle). Adverse events (AE) and tumor response were assessed. PK (regorafenib and irinotecan) were evaluated using a population PK model.We enrolled 21 patients [median age, 10 years; 12, RMS; 5, Ewing sarcoma (EWS)]. The MTD/RP2D of regorafenib in the sequential schedule was 82 mg/m2. The concomitant dosing schedule was discontinued because of dose-limiting toxicities in 2 of 2 patients treated. Most common grade 3/4 (>30% of patients) AEs were neutropenia, anemia, thrombocytopenia, and leukopenia. The overall response rate was 48% and disease control rate [complete response (CR)/partial response/stable disease/non-CR/non-progressive disease] was 86%. Median progression-free survival was 7.0 months [95% confidence interval (CI), 2.9-14.8] and median overall survival was 8.7 months (95% CI, 5.5-16.3). When combined with VI, regorafenib PK was similar to single-agent PK in children and adults (treated with regorafenib 160 mg/day).Regorafenib can be combined sequentially with standard dose VI in pediatric patients with relapsed/refractory solid tumors with appropriate dose modifications. Clinical activity was observed in patients with RMS and EWS (ClinicalTrials.gov NCT02085148).
Sequencing‐based analysis of clonal evolution of 25 mantle cell lymphoma patients at diagnosis and after failure of standard immunochemotherapy
Authors: J. Karolová, D. Kazantsev, M. Svatoň, L. Tušková, K. Forsterová, D. Maláriková, K. Benešová, T. Heizer, A. Dolníková, M. Klánová, L. Winkovska, K. Svobodová, J. Hojný, E. Krkavcová, E. Froňková, Z. Zemanová, M. Trněný, P. Klener
Journal: American Journal of Hematology (2023)

Our knowledge of genetic aberrations, that is, variants and copy number variations (CNVs), associated with mantle cell lymphoma (MCL) relapse remains limited. A cohort of 25 patients with MCL at diagnosis and the first relapse after the failure of standard immunochemotherapy was analyzed using whole-exome sequencing. The most frequent variants at diagnosis and at relapse comprised six genes: TP53, ATM, KMT2D, CCND1, SP140, and LRP1B. The most frequent CNVs at diagnosis and at relapse included TP53 and CDKN2A/B deletions, and PIK3CA amplifications. The mean count of mutations per patient significantly increased at relapse (n = 34) compared to diagnosis (n = 27). The most frequent newly detected variants at relapse, LRP1B gene mutations, correlated with a higher mutational burden. Variant allele frequencies of TP53 variants increased from 0.35 to 0.76 at relapse. The frequency and length of predicted CNVs significantly increased at relapse with CDKN2A/B deletions being the most frequent. Our data suggest, that the resistant MCL clones detected at relapse were already present at diagnosis and were selected by therapy. We observed enrichment of genetic aberrations of DNA damage response pathway (TP53 and CDKN2A/B), and a significant increase in MCL heterogeneity. We identified LRP1B inactivation as a new potential driver of MCL relapse.
Pesticides
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Sesame eliciting and safe doses in a large sesame allergic population
Authors: Liat Nachshon, Joost Westerhout, W. Marty Blom, Benjamin Remington, Michael B. Levy, Michael R. Goldberg, Naama Epstein‐Rigbi, Yitzhak Katz, Arnon Elizur
Journal: Allergy (2023)

Abstract Background Sesame is a significant food allergen causing severe and even fatal reactions. Given its increasing prevalence in western diet, sesame is listed as an allergenic food requiring labeling in the United States and EU. However, data on the population reaction doses to sesame are limited. Methods All sesame oral food challenges (OFCs), performed either for diagnosis or for threshold identification before the beginning of sesame oral immunotherapy (OIT) between November 2011 and July 2021 in Shamir medical center were analyzed for reaction threshold distribution. Safe‐dose challenges with 90–120 min intervals were also analyzed. Results Two hundred and fifty patients underwent 338 positive OFCs, and additional 158 safe‐dose OFCs were performed. The discrete and cumulative protein amounts estimated to elicit an objective reaction in 1% (ED01) of the entire cohort ( n = 250) were 0.8 mg (range 0.3–6.3) and 0.7 mg (range 0.1–7.1), respectively, and those for 5% of the population (ED05) were 3.4 mg (range 1.2–20.6) and 4.5 mg (range 1.2–28.8), respectively. Safe‐dose OFCs showed similar values of ED01 (0.8, 0.4–7.5 mg) and ED05 (3.4, 1.2–22.9 mg). While doses of ≤1 mg sesame protein elicited oral pruritus in 11.6% of the patients, no objective reaction was documented to this amount in any of the challenges, including safe‐dose OFCs. Conclusions This study provides data on sesame reaction threshold distribution in the largest population of allergic patients studied, with no right or left censored data, and with validation using a safe‐dose OFC. It further supports the current methods for ED determination as appropriate for establishing safety precautions for the food industry.
The Direct and Indirect Influences of Interrelated Regional-Level Sociodemographic Factors on Heat-Attributable Mortality in Europe: Insights for Adaptation Strategies
Authors: Simon J. Lloyd, Marcos Quijal-Zamorano, Hicham Achebak, Shakoor Hajat, Raya Muttarak, Erich Striessnig, Joan Ballester
Journal: Environmental Health Perspectives (2023)

Heat is a significant cause of mortality, but impact patterns are heterogenous. Previous studies assessing such heterogeneity focused exclusively on risk rather than heat-attributable mortality burdens and assume predictors are independent.We assessed how four interrelated regional-level sociodemographic predictors-education, life expectancy, the ratio of older to younger people (aging index), and relative income-influence heterogeneity in heat-attributable mortality burdens in Europe and then derived insights into adaptation strategies.We extracted four outcomes from a temperature-mortality study covering 16 European countries: the rate of increase in mortality risk at moderate and extreme temperatures (moderate and extreme slope, respectively), the minimum mortality temperature percentile (MMTP), and the underlying mortality rate. We used structural equation modeling with country-level random effects to quantify the direct and indirect influences of the predictors on the outcomes.Higher levels of education were directly associated with lower heat-related mortality at moderate and extreme temperatures via lower slopes and higher MMTPs. A one standard deviation increase in education was associated with a -0.46±0.14, -0.41±0.12, and 0.41±0.12 standard deviation (±standard error) change in the moderate slope, extreme slope, and MMTP, respectively. However, education had mixed indirect influences via associations with life expectancy, the aging index, and relative income. Higher life expectancy had mixed relations with heat-related mortality, being associated with higher risk at moderate temperatures (0.33±0.11 for the moderate slope; -0.19±0.097 for the MMTP) but lower underlying mortality rates (-0.72±0.097). A higher aging index was associated with higher burdens through higher risk at extreme temperatures (0.13±0.072 for the extreme slope) and higher underlying mortality rates (0.93±0.055). Relative income had relatively small, mixed influences.Our novel approach provided insights into actions for reducing the health impacts of heat. First, the results show the interrelations between possible vulnerability-generating mechanisms and suggest future research directions. Second, the findings point to the need for a dual approach to adaptation, with actions that explicitly target heat exposure reduction and actions focused explicitly on the root causes of vulnerability. For the latter, the climate crisis may be leveraged to accelerate ongoing general public health programs. https://doi.org/10.1289/EHP11766.
Preexposure Prophylaxis for the Prevention of HIV
Authors: Roger Chou, Hunter Spencer, Christina Bougatsos, Ian Blazina, Azrah Ahmed, Shelley Selph
Journal: JAMA (2023)

Importance A 2019 review for the US Preventive Services Task Force (USPSTF) found oral preexposure prophylaxis (PrEP) associated with decreased HIV infection risk vs placebo or no PrEP in adults at increased HIV acquisition risk. Newer PrEP regimens are available. Objective To update the 2019 review on PrEP, to inform the USPSTF. Data Sources Ovid MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Embase (January 2018 to May 16, 2022); surveillance through March 24, 2023. Study Selection Randomized clinical trials of PrEP vs placebo or no PrEP or newer vs older PrEP regimens and diagnostic accuracy studies of instruments for predicting incident HIV infection. Data Extraction and Synthesis Dual review of titles and abstracts, full-text articles, study quality, and data abstraction. Data were pooled using the DerSimonian and Laird random-effects model. Main Outcomes and Measures HIV acquisition, mortality, and harms; and diagnostic test accuracy. Results Thirty-two studies were included in the review (20 randomized clinical trials [N = 36 575] and 12 studies of diagnostic accuracy [N = 5 544 500]). Eleven trials in the 2019 review found oral PrEP associated with decreased HIV infection risk vs placebo or no PrEP (n = 18 172; relative risk [RR], 0.46 [95% CI, 0.33-0.66]). Higher adherence was associated with greater efficacy. One new trial (n = 5387) found oral tenofovir alafenamide/emtricitabine (TAF/FTC) to be noninferior to tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in men who have sex with men (RR, 0.53 [95% CI, 0.23-1.26]). Two new trials found long-acting injectable cabotegravir associated with decreased risk of HIV infection vs oral TDF/FTC (RR, 0.33 [95% CI, 0.18-0.62] in cisgender men who have sex with men and transgender women [n = 4490] and RR, 0.11 [95% CI, 0.04-0.31] in cisgender women [n = 3178]). Discrimination of instruments for predicting incident HIV infection was moderate in men who have sex with men (5 studies; n = 25 488) and moderate to high in general populations of persons without HIV (2 studies; n = 5 477 291). Conclusions and Relevance In adults at increased HIV acquisition risk, oral PrEP was associated with decreased risk of acquiring HIV infection compared with placebo or no PrEP. Oral TAF/FTC was noninferior to oral TDF/FTC, and injectable cabotegravir reduced the risk of HIV infection compared with oral TDF/FTC in the populations studied.